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Background and Aims: The mechanisms governing the progression of non‐alcoholic fatty liver disease (NAFLD) towards steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain elusive. Here, we evaluated the role of hsa‐miRNA‐21‐5p in NASH‐related hepatocarcinogenesis. Methods: Hepatic hsa‐miR‐21‐5p expression was evaluated in two cohorts of patients with biopsy‐proven NAFLD (n = 199) or HCC (n = 366 HCC and n = 11 NAFLD‐HCC). Serum/liver metabolomic profiles were correlated with hsa‐miR‐21‐5p in NAFLD obese patients. Wild‐type (WT) and Mir21 KO mice were fed a choline‐deficient, amino acid‐defined (CDAA) diet for 32 and 66 weeks to induce NASH and NASH‐HCC, respectively. Results: In obese individuals, hsa‐miR‐21‐5p expression increased with NAFLD severity and associated with a hepatic lipotoxic profile. CDAA‐fed WT mice displayed increased hepatic mmu‐miR‐21‐5p levels and progressively developed NASH and fibrosis, with livers presenting macroscopically discernible pre‐neoplastic nodules, hyperplastic foci and deregulated cancer‐related pathways. Mir21 KO mice exhibited peroxisome‐proliferator‐activated receptor α (PPARα) activation, augmented mitochondrial activity, reduced liver injury and NAS below the threshold for NASH diagnosis, with the pro‐inflammatory/fibrogenic milieu reversing to baseline levels. In parallel, Mir21 KO mice displayed reduced number of pre‐neoplastic nodules, hepatocyte proliferation and activation of oncogenic signalling, being protected from NASH‐associated carcinogenesis. The hsa‐miRNA‐21‐5p/PPARα pathway was similarly deregulated in patients with HCC‐ or NASH‐related HCC, correlating with HCC markers and worse prognosis. Conclusions: Hsa‐miR‐21‐5p is a key inducer of whole‐spectrum NAFLD progression, from simple steatosis to NASH and NASH‐associated carcinogenesis. The inhibition of hsa‐miR‐21‐5p, leading to a pro‐metabolic profile, might constitute an appealing therapeutic approach to ameliorate NASH and prevent progression towards HCC. [ABSTRACT FROM AUTHOR]

The nature of the immune responses associated with COVID‐19 pathogenesis and disease severity, as well as the breadth of vaccine coverage and duration of immunity, is still unclear. Given the unpredictability for developing a severe/complicated disease, there is an urgent need in the field for predictive biomarkers of COVID‐19. We have analyzed IgG Fc N‐glycan traits of 82 SARS‐CoV‐2+ unvaccinated patients, at diagnosis, by nano‐LC‐ESI‐MS. We determined the impact of IgG Fc glyco‐variations in the induction of NK cells activation, further evaluating the association between IgG Fc N‐glycans and disease severity/prognosis. We found that SARS‐CoV‐2+ individuals display, at diagnosis, variations in the glycans composition of circulating IgGs. Importantly, levels of galactose and sialic acid structures on IgGs are able to predict the development of a poor COVID‐19 disease. Mechanistically, we demonstrated that a deficiency on galactose structures on IgG Fc in COVID‐19 patients appears to induce NK cells activation associated with increased release of IFN‐γ and TNF‐α, which indicates the presence of pro‐inflammatory immunoglobulins and higher immune activation, associated with a poor disease course. This study brings to light a novel blood biomarker based on IgG Fc glycome composition with capacity to stratify patients at diagnosis. [ABSTRACT FROM AUTHOR]

The objective of this study was to compare the potential of mono‐rhamnolipids (mono‐RML) and di‐rhamnolipids (di‐RML) against biofilm formation on carbon steel coupons submitted to oil produced water for 14 days. The antibiofilm effect of the RML on the coupons was analyzed by scanning electron microscopy (SEM) and by epifluorescence microscopy, and the contact angle was measured using a goniometer. SEM analysis results showed that all RML congeners had effective antibiofilm action, as well as preliminary anticorrosion evaluation confirmed that all RML congeners prevented the metal deterioration. In more detail, epifluorescence microscopy showed that mono‐RML were the most efficient congeners in preventing microorganism's adherence on the carbon steel metal. Image analyses indicate the presence of 15.9%, 3.4%, and <0.1% of viable particles in di‐RML, mono/di‐RML and mono‐RML pretreatments, respectively, in comparison to control samples. Contact angle results showed that the crude carbon steel coupon presented hydrophobic character favoring hydrophobic molecules adhesion. We calculated the theoretical polarity of the RML congeners and verified that mono‐RML (log P = 3.63) presented the most hydrophobic character. This had perfect correspondence to contact angle results, since mono‐RML conditioning (58.2°) more significantly changed the contact angle compared with the conditioning with one of the most common surfactants used on oil industry (29.4°). Based on the results, it was concluded that rhamnolipids are efficient molecules to be used to avoid biofilm on carbon steel metal when submitted to oil produced water and that a higher proportion of mono‐rhamnolipids is more indicated for this application. [ABSTRACT FROM AUTHOR]

Because wind has a high volatility and the respective energy produced cannot be stored on a large scale because of excessive costs, it is of utmost importance to be able to forecast wind power generation with the highest accuracy possible. The aim of this paper is to compare 1‐h‐ahead wind power forecasts performance using artificial intelligence‐based methods, such as artificial neural networks (ANNs), adaptive neural fuzzy inference system (ANFIS), and radial basis function network (RBFN). The latter was implemented using three different learning algorithms: stochastic gradient descent (SGD), hybrid, and orthogonal least squares (OLS). The application dataset is the injected wind power in the Portuguese power systems throughout the years 2010–2014. The network architecture optimization and the learning algorithms are presented. An initial data analysis showed data seasonality; therefore, the wind power forecasts were performed according to the seasons of the year. The results showed that ANFIS was the best performer method, and ANN and RBFN‐OLS also showed strong performances. RBFN‐Hybrid and RBFN‐SGD performed poorly. In general, all methods outperformed persistence. [ABSTRACT FROM AUTHOR]

Rhamnolipids (RMLs) have more effectiveness for specific uses according to their homologue proportions. Thus, the novelty of this work was to compare mono‐RMLs and di‐RMLs physicochemical properties on microbial enhanced oil recovery (MEOR) applications. For this, RML produced by three strains of Pseudomonas aeruginosa containing different homologues proportion were used: a mainly mono‐RMLs producer (mono‐RMLs); a mainly di‐RMLs producer (di‐RMLs), and the other one that produces relatively balanced amounts of mono‐RML and di‐RML homologues (mono/di‐RML). For mono‐RML, the most abundant molecules were Rha‐C10C10 (m/z 503.3), for di‐RML were RhaRha‐C10C10 (m/z 649.4) and for Mono/di‐RML were Rha‐C10C10 (m/z 503.3) and RhaRha‐C10C10 (m/z 649.4). All RMLs types presented robustness under high temperature and variation of salinity and pH, and high ability for oil displacement, foam stability, wettability reversal and were classified as safe for environment according to the European Union Directive No. 67/548/EEC. For all these properties, it was observed a highlight for mono‐RML. Mono‐RML presented the lowest surface tension (26.40 mN/m), interfacial tension (1.14 mN/m), and critical micellar concentration (CMC 27.04 mg/L), the highest emulsification index (EI24 100%) and the best wettability reversal (100% with 25 ppm). In addition, mono‐RML showed the best acute toxicity value (454 mg/L), making its application potential even more attractive. Based on the results, it was concluded that all RMLs homologues studied have potential for MEOR applications. However, results showed that mono‐RML stood out and have the best mechanism of oil incorporation in micelles due their most effective surface‐active physicochemical features. [ABSTRACT FROM AUTHOR]

Direct‐acting antiviral drugs (DAAs) have recently changed the paradigm of hepatitis C therapy, significantly improving treatment response rates, patient life expectancy and quality of life. In Portugal, sofosbuvir (SOF) and SOF/ledipasvir (SOF/LDV) were fully reimbursed by the National Health System since early 2015 and generalized use of interferon‐free DAA based regimens became current practice. During 2016, the remaining DAAs were sequentially added and covered by the same health access policy. The Portuguese Study Group of Hepatitis and HIV Co‐infection (GEPCOI) collected data from 15 clinical centres in Portugal, pertaining to the HCV treatment experience with DAA regimens. A cohort of 2133 patients was analysed, representing one of the largest DAA treated HCV/HIV co‐infected individuals. The global sustained virologic response (SVR) achieved was 95% in this real‐life cohort setting. Linear regression analysis showed significant differences in treatment response rates when using SOF plus ribavirin (RBV) combination in genotype 2 or 3 infected individuals (P <.002) and in those with liver cirrhosis (P <.002). These findings corroborate that early treatment is mandatory in HIV/HCV co‐infected patients, as response rates may be negatively influenced by higher fibrosis stages and suboptimal DAA regimens. The current national Portuguese health policy should continue to promote wider treatment access and individualized therapy strategies, aiming at the elimination of HCV infection in this high‐risk co‐infected population. [ABSTRACT FROM AUTHOR]

The increased integration of wind power into the power system implies many challenges to the network operators, mainly due to the hard to predict and variability of wind power generation. Thus, an accurate wind power forecast is imperative for systems operators, aiming at an efficient and economical wind power operation and integration into the power system. This work addresses the issue of forecasting short‐term wind speed and wind power for 1 hour ahead, combining artificial neural networks (ANNs) with optimization techniques on real historical wind speed and wind power data. Levenberg‐Marquardt (LM) and particle swarm optimization (PSO) are used as training algorithms to update the weights and bias of the ANN applied to wind speed predictions. The forecasting performance produced by the proposed models are compared with each other, as well as with the benchmark persistence model. Test results show higher performance for ANN‐LM wind speed forecasting model, outperforming both ANN‐PSO and persistence. The application of ANN‐LM to wind power forecast revealed also a good performance, with an average improvement of 2.8% in relation to persistence. An innovative analysis of mean absolute percentage error (MAPE) behaviour in time and in typical days is finally offered in the paper. [ABSTRACT FROM AUTHOR]

BACKGROUND: Microbial surfactants are multifunctional surface‐active molecules that have been overlooked in formulating microbial biopesticides. We report a novel approach using the biosurfactant rhamnolipid (RML) against the destructive cosmopolitan insect pest Bemisia tabaci, as well as the combined action of RML with aerial conidia of two entomopathogenic fungi, Cordyceps javanica and Beauveria bassiana. RML was also tested as a suspension agent to improve the recovery rate of conidia from solid substrate for fungal preparations. RESULTS: The recovery rate of conidia increased dramatically (two to five times) with RML compared with a standard surfactant (Tween 80). Spraying solutions of 0.075% and 0.1% (w/v) RML on B. tabaci third instar nymphs induced 100% mortality within 4 days. Conidial suspensions at 5 × 106 conidia/mL amended with RML at 0.01% or 0.05% markedly increased nymphal mortalities and considerably reduced LC50. Conidial suspensions of B. bassiana with 0.05% RML added were more effective against whitefly nymphs (87.3% mortality) than C. javanica + RML (51.4% mortality). CONCLUSION: Our results show that this bacterium‐based RML improved the recovery rate of hydrophobic conidia, and that mixtures of RML with fungal spore suspensions increased their insecticidal activity. © 2019 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

The high mortality rate of cholangiocarcinoma (CCA) is due, in part, to the lack of non‐invasive approaches able to accurately detect this silent tumour at early stages, when therapeutic options can be potentially curative or may at least increase the overall survival of patients. The fact that the majority of CCA tumours are not linked to any known aetiological factor highly compromises the monitoring of patients at risk for tumour development and also their early diagnosis. Combination of clinical/biochemical features, imaging techniques and analysis of non‐specific tumour biomarkers in serum are commonly used to help in the diagnosis of CCA, but tumour biopsy is usually required to confirm the diagnosis. Moreover, no prognostic biomarkers are currently used in the clinical setting, deserving more innovative research, and international validation and consensus. Important efforts have been made in the last few years to identify accurate non‐invasive biomarkers, by using innovative techniques and high‐throughput omics technologies. This review summarizes and discusses the advances in the investigation of novel diagnostic and prognostic biomarkers in CCA and envisions the future directions in this field of research. [ABSTRACT FROM AUTHOR]

Despite higher winds, the investment and operation and maintenance costs of offshore wind farms are still high as compared to onshore solutions. This highlights the importance of an increased reliability, because the occurrence of a failure can result in long downtimes due to inaccessibility of the site during harsh weather conditions. This study performs a reliability analysis of the internal grid of an offshore wind farm, comparing different topologies and their economic outcome. The research addresses both a redundancy between each pair of two strings (classical redundancy design) and a redundancy between already redundantly paired sets of strings (newly proposed redundancy design). The results show that the use of a redundancy scheme leads to a positive Net Present Value (NPV) and an interesting Internal Rate of Return (IRR), which can be an appealing investment. Moreover, it is more profitable to simply rate the cables to support normal operation conditions at rated power rather than increasing the cable ratings to support all failure scenarios. Overall, the topology that shows the best economic results combined with a good reliability is the topology with cable ratings based on regular conditions with a redundancy in the middle of the string between each pair of two strings. [ABSTRACT FROM AUTHOR]

ABSTRACT: A recombinant lipase B from Candida antarctica (LipB) in Pichia pastoris was synthesized through submerged fermentation using crude glycerin as substrate. The immobilization of this enzyme on the core–shell polymeric supports is an effective alternative for its application. The supports with distinct levels of hydrophobicity were produced through combined suspension and emulsion polymerization in pilot scale. Particles with distinct compositions were synthesized (PMMA/PMMA; PMMA‐co‐DVB/PMMA‐co‐DVB; and PS‐co‐DVB/PS‐co‐DVB) and employed on the immobilization of the produced lipase (LipB) and the commercial enzyme (CalB). The morphological properties (specific area, average pore diameter, specific volume of pores, and hydrophobicity level) and the influence of the polymerization conditions on the morphology of the supports were studied. The thermal stability of such biocatalysts was also investigated in the presence of calcium cation (Ca+2), maintained 100% of the activity after 3 h at 50°C when the PMMA‐co‐DVB/PMMA‐co‐DVB was employed. The synthesized enzyme and supports manufactured in pilot scale were employed successfully for production of esters using residual fatty acids as substrates, adding value to these raw materials and increasing the ranges of possible applications. [ABSTRACT FROM AUTHOR]

Nowadays, a strong concern to decrease greenhouse gas emissions is encouraging the implementation of renewable energy sources closer to end‐users, in low‐voltage (LV) distribution networks. Due to the expected high microgeneration (µG) penetration level, several problems are likely to arise, such as overvoltages and reverse power flow. This study presents a review of the several techniques used to deal with these problems. These are compared in terms of their capacity to smooth the voltage profile and avoid reverse power flow. An unbalanced three‐phase power flow algorithm, based on current summation method for radial distribution networks, is proposed. A study based on a highly unbalanced test radial LV distribution network for a typical summer day, with a high µG penetration, is performed. The voltage profile, active power flow in the service transformer, and power losses on the network are the monitored electrical quantities. The obtained results indicate that self‐consumption with storage is the recommended solution to eliminate overvoltages, to avoid reverse power flow and allow for a decreasing in the power losses. Nevertheless, the economic viability of this solution must be carefully assessed, because the profitability of the project is not straightforward at the current time. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Ursodeoxycholic acid (UDCA) is a secondary hydrophilic bile acid (BA) used as therapy for a range of hepatobiliary diseases. Its efficacy in non‐alcoholic fatty liver disease (NAFLD) is still under debate. Here, we aimed to decipher molecular mechanisms of UDCA in regulating endoplasmic reticulum (ER) homeostasis, apoptosis and oxidative stress in morbidly obese patients. Methods: In this randomized controlled pharmacodynamic study, liver and serum samples from 40 well‐matched morbidly obese NAFLD‐patients were analysed. Patients received UDCA (20 mg/kg/d) or no treatment 3 weeks before samples were obtained during bariatric surgery. Results: Patients treated with UDCA displayed higher scoring of steatosis (S), activity (A) and fibrosis (F), the so called SAF‐scoring. UDCA partially disrupted ER homeostasis by inducing the expression of the ER stress markers CHOP and GRP78. However, ERDJ4 and sXBP1 levels were unaffected. Enhanced CHOP expression, a suggested pro‐apoptotic trigger, failed to induce apoptosis via BAK and BAX in the UDCA treated group. Potentially pro‐apoptotic miR‐34a was reduced in the vesicle‐free fraction in serum but not in liver after UDCA treatment. Thiobarbituric acid reactive substances, 4‐hydroxynonenal and mRNA levels of several oxidative stress indicators remained unchanged after UDCA treatment. Conclusion: Our data suggest that UDCA treatment has ambivalent effects in NAFLD patients. While increased SAF‐scores and elevated CHOP levels may be disadvantageous in the UDCA treated cohort, UDCA's cytoprotective properties potentially changed the apoptotic threshold as reflected by absent induction of pro‐apoptotic triggers. UDCA treatment failed to improve the oxidative stress status in NAFLD patients. [ABSTRACT FROM AUTHOR]

Photovoltaic microgeneration (μG) located near the domestic consumers is expected to increase more in the future. Known issues regarding high μG penetration are voltage rise and reverse power flow. The concept of selfconsumption and storage is emerging as a way to improve network power supply quality and to facilitate the integration of small renewable energy sources in low voltage networks. This paper intends to give a further contribution by assessing the improvements provided by allowing domestic clients to consume and store the energy they produce. The tool at hand to study the situation is the unbalanced three-phase load flow algorithm, based on the power summation technique, improved with the capability of explicitly compute the neutral voltages. The behaviour of a test radial distribution grid is assessed in different operating conditions, namely winter/summer, μG penetration level and μG operating mode. Voltage profile, active power flow in the service transformer and losses are monitored. The results suggest that self-consumption with storage operating mode is a promising solution. Voltage excursions above normal grid voltage operating limits were not observed, the situation of reverse active power flow does not occur and the power losses are reduced. [ABSTRACT FROM AUTHOR]

We estimate the volatility of plant-level idiosyncratic shocks in U.S. manufacturing. We measure the variation in Revenue Total Factor Productivity not explained by either industry or economy-wide factors, or by establishments' characteristics. We find that idiosyncratic shocks are much larger than aggregate shocks, accounting for about 80% of the overall uncertainty faced by plants. Plants in the most volatile sector are subject to about six times as much idiosyncratic uncertainty as plants in the least volatile. We provide evidence suggesting that idiosyncratic risk is higher in industries where the extent of creative destruction is likely to be greater. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease ( NAFLD) comprises a spectrum of stages from simple steatosis to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and, ultimately, hepatocellular carcinoma. Despite being one of the most common chronic liver diseases, NAFLD pathogenesis remains largely unknown. In this review, we discuss the key molecular mechanisms involved in NAFLD development and progression, focusing on the emerging role of micro RNAs. NAFLD is intrinsically related to obesity and the metabolic syndrome. Changes in lipid metabolism increase free fatty acids in blood, which in turn induces peripheral insulin resistance and increases oxidative and endoplasmic reticulum stress. Although not yet considered in the diagnosis of NAFLD, recent reports also reinforce the crucial role of apoptosis in disease progression via activation of either death receptor or mitochondrial pathways and p53. In addition, the role of gut microbiota and the gut-liver axis has been recently associated with NAFLD. Finally, there is an accumulating and growing body of evidence supporting the role of micro RNAs in NAFLD pathogenesis and progression, as well as hinting at their use as biomarkers or therapeutic tools. The ultimate goal is to review different molecular pathways that may underlie NAFLD pathogenesis in the hope of finding targets for new and efficient therapeutic interventions. [ABSTRACT FROM AUTHOR]

We introduce a new protocol to obtain very high-frame-rate cinematographic (Cine) MRI movies of the beating mouse heart within a reasonable measurement time. The method is based on a self-gated accelerated fast low-angle shot (FLASH) acquisition and compressed sensing reconstruction. Key to our approach is that we exploit the stochastic nature of the retrospective triggering acquisition scheme to produce an undersampled and random k-t space filling that allows for compressed sensing reconstruction and acceleration. As a standard, a self-gated FLASH sequence with a total acquisition time of 10 min was used to produce single-slice Cine movies of seven mouse hearts with 90 frames per cardiac cycle. Two times (2×) and three times (3×) k-t space undersampled Cine movies were produced from 2.5- and 1.5-min data acquisitions, respectively. The accelerated 90-frame Cine movies of mouse hearts were successfully reconstructed with a compressed sensing algorithm. The movies had high image quality and the undersampling artifacts were effectively removed. Left ventricular functional parameters, i.e. end-systolic and end-diastolic lumen surface areas and early-to-late filling rate ratio as a parameter to evaluate diastolic function, derived from the standard and accelerated Cine movies, were nearly identical. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

MicroRNAs are aberrantly expressed in cancer; microRNA-143 (miR-143) is down-regulated in colon cancer. HCT116 human colorectal cancer cells were used to investigate the biological role of miR-143. Transient miR-143 overexpression resulted in an approximate 60% reduction in cell viability. In addition, stable miR-143 overexpressing cells were selected with G418 and exposed to 5-fluorouracil. Increased stable expression of miR-143 was associated with decreased viability and increased cell death after exposure to 5-fluorouracil. These changes were associated with increased nuclear fragmentation and caspase -3, -8 and -9 activities. In addition, extracellular-regulated protein kinase 5, nuclear factor-κB and Bcl-2 protein expression was down-regulated by miR-143, and further reduced by exposure to 5-fluorouracil. In conclusion, miR-143 modulates the expression of key proteins involved in the regulation of cell proliferation, death and chemotherapy response. In addition, miR-143 increases the sensitivity of colon cancer cells to 5-fluorouracil, probably acting through extracellular-regulated protein kinase 5/nuclear factor-κB regulated pathways. Collectively, the data obtained in the present study suggest anti-proliferative, chemosensitizer and putative pro-apoptotic roles for miR-143 in colon cancer. [ABSTRACT FROM AUTHOR]

We document and discuss a dramatic change in the cyclical behavior of aggregate skilled hours since the mid-1980s. Using CPS data for 1979:1–2003:4, we find that the volatility of skilled hours relative to the volatility of GDP has nearly tripled since 1984. In contrast, the cyclical properties of unskilled hours have remained essentially unchanged. We evaluate whether a simple supply/demand model for skilled and unskilled labor with capital-skill complementarity in production can help explain this stylized fact. Our model accounts for about 60% of the observed increase in the relative volatility of skilled labor. [ABSTRACT FROM AUTHOR]

Early onset familial Alzheimer's disease (FAD) is linked to autosomal dominant mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2) genes. These are critical mediators of total amyloid β-peptide (Aβ) production, inducing cell death through uncertain mechanisms. Tauroursodeoxycholic acid (TUDCA) modulates exogenous Aβ-induced apoptosis by interfering with E2F-1/p53/Bax. Here, we used mouse neuroblastoma cells that express either wild-type APP, APP with the Swedish mutation (APPswe), or double-mutated human APP and PS1 (APPswe/ΔE9), all exhibiting increased Aβ production and aggregation. Cell viability was decreased in APPswe and APPswe/ΔE9 but was partially reversed by z-VAD.fmk. Nuclear fragmentation and caspase 2, 6 and 8 activation were also readily detected. TUDCA reduced nuclear fragmentation as well as caspase 2 and 6, but not caspase 8 activities. p53 activity, and Bcl-2 and Bax changes, were also modulated by TUDCA. Overexpression of p53, but not mutant p53, in wild-type and mutant neuroblastoma cells was sufficient to induce apoptosis, which, in turn, was reduced by TUDCA. In addition, inhibition of the phosphatidylinositide 3′-OH kinase pathway reduced TUDCA protection against p53-induced apoptosis. In conclusion, FAD mutations are associated with the activation of classical apoptotic pathways. TUDCA reduces p53-induced apoptosis and modulates expression of Bcl-2 family. [ABSTRACT FROM AUTHOR]

How does openness affect economic development? This question is answered in the context of a dynamic general equilibrium model of the world economy, where countries have technological differences that are both sector neutral and specific to the investment goods sector. Relative to a benchmark case of trade in credit markets only, consider (i) a complete restriction of trade and (ii) a full liberalization of trade. The first change decreases the cross-sectional dispersion of incomes only slightly, and produces a relatively small welfare loss. The second change, instead, decreases dispersion by a significant amount, and produces a very large welfare gain. [ABSTRACT FROM AUTHOR]

Amyloid β-peptide (Aβ)-induced cell death may involve activation of the E2F-1 transcription factor and other cell cycle-related proteins. In previous studies, we have shown that tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, modulates Aβ-induced apoptosis by interfering with crucial events of the mitochondrial pathway. In this study, we examined the role of E2F and p53 activation in the induction of apoptosis by Aβ, and investigated novel molecular targets for TUDCA. The results showed that despite Bcl-2 up-regulation, PC12 neuronal cells underwent significant apoptosis after incubation with the active fragment Aβ (25–35), as assessed by DNA fragmentation, nuclear morphology and caspase-3-like activation. In addition, transcription through the E2F-1 promoter was significantly induced and associated with loss of the retinoblastoma protein. In contrast, levels of E2F-1, p53 and Bax proteins were markedly increased. Overexpression of E2F-1 in PC12 cells was sufficient to induce p53 and Bax proteins, as well as nuclear fragmentation. Notably, TUDCA modulated Aβ-induced apoptosis, E2F-1 induction, p53 stabilization and Bax expression. Further, TUDCA protected PC12 cells against p53- and Bax-dependent apoptosis induced by E2F-1 and p53 overexpression, respectively. In conclusion, the results demonstrate that Aβ-induced apoptosis of PC12 cells proceeds through an E2F-1/p53/Bax pathway, which, in turn, can be specifically inhibited by TUDCA, thus underscoring its potential therapeutic use. [ABSTRACT FROM AUTHOR]

We propose an explanation for why efficient reforms are not carried out when losers can block their implementation and compensations are feasible. In our model, a government tries to sequentially implement two efficient reforms by bargaining with interest groups. The organization of interest groups is endogenous. Compensations are distortionary and different governments care differently about distortions. Governments use low compensations to discourage losers who just want to receive transfers from organizing. This comes at the cost of reforms being blocked by interest groups with relatively high losses, resulting in a bias against payment of compensations and the implementation of reforms. [ABSTRACT FROM AUTHOR]